Project Summary Over the past 15 years, the SPORE in Prostate Cancer at Memorial Sloan Kettering Cancer Center has made significant advances in prostate cancer research and treatment, using the evolving mechanistic understanding of the drivers of tumor growth to improve patient management across the clinical spectrum of the disease. Applying a risk-adapted approach that is biomarker based, our work has led to the development of new diagnostic blood tests and prognostic models to distinguish indolent from clinically significant cancers, the discovery of new therapeutic targets, their validation in preclinical models, and the successful development of drugs directed to them in trials designed according to the recommendations of the Prostate Cancer Working Group. Our efforts have impacted clinical practice worldwide. Recent discoveries enabled by state-of-the-art molecular profiling and bioinformatics, combined with a commitment by the research community to obtain human prostate cancers representing all clinical states for analysis, are leading rapidly to a biology-based taxonomy that will further refine medical decision making?personalized, precision medicine. Over the next 5 years, our program will continue to focus on defining the mechanisms that contribute to disease progression and resistance to therapy, developing validated assays to identify them in patient tumors that can be used in a clinical setting, designing dedicated biomarker trials to validate them clinically, and demonstrating their utility to inform medical decision making. We are confident that our efforts will not only improve patient outcomes but will enable urgently needed new systemic therapies to be successfully developed more rapidly. Our SPORE is organized into 5 major research projects that are tightly integrated to achieve the overall objectives. Each is headed by a basic and a clinical investigator who lead a multidisciplinary team that was chosen for its outstanding translational potential and ability to address critical unmet patient needs. This ?team science? approach extends beyond the boundaries of our program to include vital collaborations with other institutions and networks, federal agencies, and industry, including other SPOREs and translational science programs, the Department of Defense Transformative Impact Award, which brings together pathologists and clinical oncologists from 5 prostate SPOREs to analytically validate tissue based predictive biomarker assays, and the Prostate Cancer Clinical Trials Consortium, which virtually guarantees that important basic and clinical discoveries made and developed through our SPORE and in our research network are translated to reach human endpoints quickly and efficiently.